Targeted Knockdown of Epithelial Estrogen Receptor α to Mitigate Ferroptosis and Epithelial–Mesenchymal Transition in Eosinophilic Asthma

Estrogen receptor α (ERα) is involved with the hyperresponsiveness and airway remodeling in asthma, but developing therapies targeting ERα remains challenging due to its multifaceted roles in different cell types and the poor efficacy of systemic ERα intervention in asthma. Previously, we uncovered the association of increased ERα expression in airway epithelial cells with poor pulmonary function and epithelial-mesenchymal transition (EMT) in asthma patients. This study further investigated the association of ERα expression with the ferroptosis and EMT levels in a cohort of eosinophilic asthma (EA) patients as well as in an eosinophil-epithelial coculture cell model. By loading small interfering RNA (siRNA) into a mesoporous silica nanoparticle (MSN) and then coating the extracted bronchial epithelial cytomembrane (CM), a bronchial epithelial CM home-targeting nanoplatform (siRNA@MSN@CM) was constructed to selectively decrease the ERα expression in bronchial epithelial cells. The targeting effect of bronchial epithelial cells was confirmed in vitro and in vivo, demonstrating the successful targeted knockdown of ERα expression. Silencing ERα in epithelial cells effectively prevented ferroptosis and EMT induced by coculturing with ferroptotic eosinophils. Targeted intervention of epithelium ERα with intratracheal delivery of siRNA(ERα)@MSN@CM nanoparticle significantly reduced the levels of ferroptosis in bronchial epithelial cells, airway inflammation, and airway remodeling in asthmatic mouse models. This study introduces an innovative nanomaterial for targeted drug delivery to epithelial cells and underscores the potential of targeted knockdown ERα in bronchial epithelial cells as a therapeutic strategy for asthma treatment.